Electrocatalytic continuous flow chlorinations with iodine(I/III) mediators

Electrochemistry offers tunable, cost effective and environmentally friendly alternatives to carry out redox reactions with electrons as traceless reagents. The use of organoiodine compounds as electrocatalysts is largely underdeveloped, despite their widespread application as powerful and versatile reagents. Mechanistic data reveal that the hexafluoroisopropanol assisted iodoarene oxidation is followed by a stepwise chloride ligand exchange for the catalytic generation of the dichloroiodoarene mediator. Here, we report an environmentally benign iodine(I/III) electrocatalytic platform for the in situ generation of dichloroiodoarenes for different reactions such as mono- and dichlorinations as well as chlorocyclisations within a continuous flow setup.


REVIEWER COMMENTS
Reviewer #1 (Remarks to the Author): In this manuscript, Wirth and coauthors report an environmentally benign iodine(I/III) electrocatalytic platform for the in-situ generation of dichloroiodoarenes (ArICl2), which was suitable for various reactions such as mono-and dichlorinations as well as chlorocyclizations within a continuous flow setup.This strategy demonstrates that mechanistic data reveal the hexafluoroisopropanol assisted iodoarene oxidation is followed by a stepwise chloride ligand exchange for the catalytic generation of the ArICl2 mediator.However, the authors do not sufficiently investigate the specific process of chlorination of the substrates, and the mechanistic study needs to be improved.Furthermore, the authors have not conducted further research on the applicability of this method, such as the derivatization of the products.From conceptual aspect, there are several works have been published (see J. Am.Chem.Soc.2017, 139, 15548-15553; Acc.Chem.Res.2020, 53, 3, 547-560).Overall, I think this work is not suitable to be published in Nature Communications.To improve the quality of this manuscript, there are some comments and suggestions should be addressed: 1.In Table 2, concerning the carboxylic acid cyclization reactions, is the mechanism similar to the dichlorination of olefins?Is it possible that a dichlorinated intermediate is first formed, followed by an intramolecular nucleophilic substitution to yield the product, or does a monochlorinated intermediate first form, which then undergoes oxidation to generate a carbocation that subsequently undergoes intramolecular cyclization to form the product?Additionally, the monochlorination of 1,3-dicarbonyl compounds: is this a radicaltype reaction, or an ionic-type reaction?2. Whether the intermediate 2a has been identified?3.In the introduction of the manuscript, the novelty of the experimental method is confusing and requires further emphasis on the characteristics of the reaction.4. Why hexafluoroisopropanol plays a significant role in the chlorination process is not further explained in the mechanistic study.
5. The experimental study in Figure 3d does not provide any supportive evidence for the mechanistic study.

Reviewer #2 (Remarks to the Author):
This is a good paper and can be published in Nature Communications.While flow electrochemistry in concert with catalytic hypervalent iodine is known (indeed developed by these authors), the lack of chlorination methods using flow Echem makes this report an important advance.That the technique works is not particularly surprising, all the individual components have been known for some time, but it is good to see ArICl2 chlorination and flow electrochemical catalysis brought toghether.TMS-Cl is an attractive chloride source, as this is often waste for other chemical reactions and a low-energy source.
A particular strength of this paper is the supporting information.It is sublime.All the details are given, including photos of the set-up.Even more impressive is that the authors have presented imperfect spectra and simply pointed out cases where overlapping peaks etc prevent firm assignments -we need to see more of this in the literature, rather than feeling pressure to always produce special perfect spectra for the SI.

Reviewer #3 (Remarks to the Author):
This manuscript by Wirth and co-workers describes a very attractive method to enable the mono-, di-and chlorocyclisation of an array of simple, unfunctionalized substrates through an electrocatalytic flow platform.The reaction relies on an I(I)/I(III) cycle and utilises inexpensive 4-iodotoluene as the catalyst (25 mol%) with TMSCl (4 eq.) serving as the chloride source.In situ generation of pTolICl2 is achieved electrochemically (graphite electrodes) with HFIP assisting the oxidation and being replaced by Cl through ligand exchange at the iodine centre.The introduction of the paper is compelling and I commend the authors on highlighting the pioneering work of Willgerodt, after whom the parent reagent (PhICl2) is named.The authors may also wish to cite recent structural work on this reagent (Synthesis 2019, 51, 4408-4416).Seminal contributions from the labs of Power and Xu are also prominently cited and I find this both refreshing and scholarly.As shown in Figure 1, the key advances of this chemistry include the in-cell application (as opposed to excell approaches for the preparation of I(III) intermediates), the low electrolyte concentration, metal-free conditions and comparatively low catalyst loadings of pTolI.
Collectively, these are significant advances in a very active field of contemporary research.
The selection of catalyst and chloride source as convincingly demonstrated in Figure 2 and the advantages of TMSCl in terms of facile ligand exchange to generate the ArICl2 product far outweigh any concerns regarding atom economy.Similarly, the choice of graphite electrodes is demonstrated in the vicinal dichlorination of alkene 4 (to form 5 in 80% yield) and the scope in Table 2 is  We are very thankful for the positive comments and suggestions of all reviewers.Our detailed feedback and comments are below.

Statements:
In this manuscript, Wirth and coauthors report an environmentally benign iodine(I/III) electrocatalytic platform for the in-situ generation of dichloroiodoarenes (ArICl2), which was suitable for various reactions such as mono-and dichlorinations as well as chlorocyclizations within a continuous flow setup.This strategy demonstrates that mechanistic data reveal the hexafluoroisopropanol assisted iodoarene oxidation is followed by a stepwise chloride ligand exchange for the catalytic generation of the ArICl2 mediator.However, the authors do not sufficiently investigate the specific process of chlorination of the substrates, and the mechanistic study needs to be improved.Furthermore, the authors have not conducted further research on the applicability of this method, such as the derivatization of the products.From conceptual aspect, there are several works have been published (see J. Am.Chem.Soc.2017, 139, 15548-15553;  Acc.Chem.Res.2020, 53, 3, 547-560).Overall, I think this work is not suitable to be published in Nature Communications.To improve the quality of this manuscript, there are some comments and suggestions should be addressed:

Response to the statements of Reviewer 1:
We thank the reviewer for providing comments and suggestions to improve the quality of the manuscript.The first reference above was already included in our manuscript (ref.23), the second one is now also included as reference 24.
Comment 1-1: "In Table 2, concerning the carboxylic acid cyclization reactions, is the mechanism similar to the dichlorination of olefins?Is it possible that a dichlorinated intermediate is first formed, followed by an intramolecular nucleophilic substitution to yield the product, or does a monochlorinated intermediate first form, which then undergoes oxidation to generate a carbocation that subsequently undergoes intramolecular cyclization to form the product?Additionally, the monochlorination of 1,3-dicarbonyl compounds: is this a radical-type reaction, or an ionic-type reaction?" Response: In response to the reviewer's question, we have verified the involvement of a dichlorinated intermediate in the chlorocyclization reaction through independent synthesis of the starting material.The result of this mechanistic experiment is now included in Figure 3e.The following statement is now included in the manuscript (page 5): A dichlorination followed by intramolecular substitution can be ruled out for chlorocyclisation reactions as the γ,δ-dichlorinated acid failed to provide 33 under the standard electrochemical reaction conditions (Fig. 3e).
Additionally, we investigated the involvement of radicals in the monochlorination and found the results to be similar to those to the dichlorination reactions.This data is now included in the supplementary information (Page 13, Figure 6).Also, we have included further points and references to clarify the mechanism in detail in the revised manuscript (page 5): Such partial radical nature for dichlorination reactions could also be converged from the fact that both E-and Z-alkenes returned mixture of diastereomers (Table 2, entries 26-29).Notably, 3a is also known to act in radical chlorination processes 57 .Comment 1-2: "Whether the intermediate 2a has been identified?" Response: Intermediate 2a was identified through spectroscopic analysis, as already detailed in the original manuscript on page 4, after ((Figure 3)): Intriguingly, the unsymmetrical hypervalent iodine intermediate 2a was successfully identified (Fig. 3a) 56 .
The relevant spectroscopic data can be found in the supplementary information, Figures 3 and 4.
Comment 1-3: "In the introduction of the manuscript, the novelty of the experimental method is confusing and requires further emphasis on the characteristics of the reaction."

Response:
In response to the reviewer's comment, we emphasize that the in-cell flow electrocatalytic generation and use of hypervalent iodine compound for chlorination reactions are novel aspects of this work.We hope that we have highlighted this unambiguously in the introduction.Only considering the chlorination methodology by overlooking the key iodine (I/III) electrocatalysis part is only a partial evaluation of this work.
Comment 1-4: "Why hexafluoroisopropanol plays a significant role in the chlorination process is not further explained in the mechanistic study."

Response:
We have now included a more detailed discussion on the crucial role of HFIP in the mechanistic section (page 5): HFIP plays multiple roles in this reaction.Firstly, HFIP has excellent anodic stability and high conductivity suitable for electrochemical oxidation of aryl iodide.Secondly, HFIP is known to play an active role in stabilizing electrochemically generated iodine(III) compounds 7,11,20,45 .Thirdly, the low pKa (9.4) of HFIP allows clean proton reduction as the cathodic half-reaction rendering only H2 as the byproduct of this electrochemical process.Finally, the non-nucleophilic and polar HFIP has a positive impact on the rate and selectivity of transformations involving radical and ionic intermediates and hence is often used in iodine(III)-mediated reactions 40,58 .
Comment 1-5: "The experimental study in Figure 3d does not provide any supportive evidence for the mechanistic study." Response: Figure 3d only indicates that a parallel radical pathway could be operative to the ionic one which is further supported by the diastereomeric ratio obtained for unsymmetrical alkenes (such as products 26 and 27) as well as by previous reported literature.We have added this discussion and references on page 5: Such partial radical nature for dichlorination reactions could also be converged from the fact that both E-and Z-alkenes returned mixture of diastereomers (Table 2, entries 26-29).Notably, 3a is also known to act in radical chlorination processes 57 .

Response:
We thank the referee for bringing these papers to our attention, we have added these valuable references as 44 and 45 in the revised manuscript.

Statements:
This is a good paper and can be published in Nature Communications.While flow electrochemistry in concert with catalytic hypervalent iodine is known (indeed developed by these authors), the lack of chlorination methods using flow Echem makes this report an important advance.That the technique works is not particularly surprising, all the individual components have been known for some time, but it is good to see ArICl2 chlorination and flow electrochemical catalysis brought toghether.TMS-Cl is an attractive chloride source, as this is often waste for other chemical reactions and a low-energy source.A particular strength of this paper is the supporting information.It is sublime.All the details are given, including photos of the set-up.Even more impressive is that the authors have presented imperfect spectra and simply pointed out cases where overlapping peaks etc prevent firm assignments -we need to see more of this in the literature, rather than feeling pressure to always produce special perfect spectra for the SI.

Response to the statements of Reviewer 2:
We greatly appreciate the high evaluation of our work and positive feedback.This reviewer did not raise any point to address and is in favour of accepting this work in its current form.

Statements:
This manuscript by Wirth and co-workers describes a very attractive method to enable the mono-, di-and chlorocyclisation of an array of simple, unfunctionalized substrates through an electrocatalytic flow platform.The reaction relies on an I(I)/I(III) cycle and utilises inexpensive 4-iodotoluene as the catalyst (25 mol%) with TMSCl (4 eq.) serving as the chloride source.In situ generation of pTolICl2 is achieved electrochemically (graphite electrodes) with HFIP assisting the oxidation and being replaced by Cl through ligand exchange at the iodine centre.The introduction of the paper is compelling and I commend the authors on highlighting the pioneering work of Willgerodt, after whom the parent reagent (PhICl2) is named.The authors may also wish to cite recent structural work on this reagent (Synthesis 2019, 51, 4408-4416).Seminal contributions from the labs of Power and Xu are also prominently cited and I find this both refreshing and scholarly.As shown in Figure 1, the key advances of this chemistry include the in-cell application (as opposed to ex-cell approaches for the preparation of I(III) intermediates), the low electrolyte concentration, metal-free conditions and comparatively low catalyst loadings of pTolI.Collectively, these are significant advances in a very active field of contemporary research.The selection of catalyst and chloride source as convincingly demonstrated in Figure 2 and the advantages of TMSCl in terms of facile ligand exchange to generate the ArICl2 product far outweigh any concerns regarding atom economy.Similarly, the choice of graphite electrodes is demonstrated in the vicinal dichlorination of alkene 4 (to form 5 in 80% yield) and the scope in Table 2 is very convincing.Examples of 1,2-dichlorination (with both internal and terminal alkenes), chlorolactonisation and the alpha chlorination of 1,3-dicarbonyl compounds has been validated.The postulated mechanism is supported by mechanistic work and this includes (1) a demonstration of stepwise chloride exchange), (2) a stoichiometric comparison (with and without the HFIP) and the addition of BHT and TEMPO as radical traps.

Response to the statements of Reviewer 3:
We appreciate this reviewer's recommendation of our research.This reviewer's suggestions were extremely encouraging, and they indeed helped us to improve our manuscript.A point-by-point response to this reviewer's suggestion/comments is given below.

Response:
We have now cited this work as reference 5, with the relevant discussion included on page 1, first paragraph.
However, improvement of the stability of this class of reagents through structural analysis is explored continuously to further exploit their reactivities 5 .Comment 3-2: "My only slight concern is the potential for uncatalyzed background reactions with highly electron-rich alkenes (e.g. 29, 30 and 31), as this is known with many halofunctionalisation reactions using stoichiometric oxidants.It would be helpful to run controls in these cases." Response: We thank the reviewer for pointing this out.We have carried out the corresponding control reactions for the highly electron rich alkenes as suggested by the reviewer.Indeed, a larger rate of uncatalysed background reactions were observed.However, the differences in yields between catalysed and uncatalysed reactions are very convincing.Examples of 1,2-dichlorination (with both internal and terminal alkenes), chlorolactonisation and the alpha chlorination of 1,3dicarbonyl compounds has been validated.The postulated mechanism is supported by mechanistic work and this includes (1) a demonstration of stepwise chloride exchange), (2) a stoichiometric comparison (with and without the HFIP) and the addition of BHT and TEMPO as radical traps.My only slight concern is the potential for uncatalyzed background reactions with highly electron-rich alkenes (e.g. 29, 30 and 31), as this is known with many halofunctionalisation reactions using stoichiometric oxidants.It would be helpful to run controls in these cases.Since the very moderate enantioselectivity has been reported in the vicinal dichlorination of alkenes by Gilmour (cited as reference 37), I am curious to know if the authors tried a chiral ArI catalyst in any of the transformations reported?Can the authors comment a little more on the role of the HFIP in the oxidation step?This is interesting and potentially expansive.Overall, I really enjoyed reading this paper and I recommend publication of the work in Nature Communications.The chemistry is clearly powerful, well-demonstrated and residence times of 12 minutes far outcompetes conventional approaches! 1 Revision of manuscript id NCOMMS-24-17595 (Electrocatalytic Continuous Flow Chlorinations with Iodine(I/III) Mediators)